A role for B cells in autoimmune diseases is now clearly established both with mouse models as well as in humans by successful treatment of rheumatoid arthritis (RA) and other autoimmune diseases with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells may promote the development of autoimmune diseases remain poorly understood. We previously demonstrated that untreated active RA patients, patients with systemic lupus erythematosus, and patients with type 1 diabetes display abnormal early B cell tolerance checkpoints resulting in the accumulation of large numbers of autoreactive naove B cells in their blood. We recently established that these early B cell tolerance defects were primary to these autoimmune diseases and can be induced in asymptomatic donors by risk alleles such as PTPN22, which interfere with B cell receptor (BCR) signaling and the establishment of central B cell tolerance. In addition, anergy, one of the central B cell tolerance mechanisms, seems to be favored in some RA patients as illustrated by the increased frequency of peripheral unresponsive autoreactive B cells, which do not express the complement receptor 2/CD21 and are refractory to BCR and CD40 triggering. Hence, increased numbers of naove autoreactive B cells in patients with RA may favor disease development but it remains to be determined what pathways and mechanisms break B cell tolerance. The long range goal of the proposed research is to continue to characterize the mechanisms that regulate B cell tolerance in healthy humans but are defective in RA patients. The working hypothesis is that RA B cells suffer from intrinsic defects caused by associated risk alleles, which impinge on sensing self-antigens and result in an altered induction/regulation of central B cell tolerance mechanisms. Hence, receptor editing and deletion fail to be properly regulated in RA patients whereas anergy also contributes to the increased numbers of autoreactive B cells reaching the periphery where inflammatory conditions such as in the synovium may lead the activation of these autoreactive B cells and promote disease development. In addition, understanding the mechanisms that prevent or account for the production of autoreactive B cells may suggest new approaches to control disease and design more specific and sustained therapies.